11 beta-hydroxysteroid dehydrogenases: A growing multi-tasking family

摘要

This review briefly addresses the history of the discovery and elucidation of the three cloned 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) enzymes in the human, 11 beta HSD1, 11 beta HSD2 and 11 beta HSD3, an NADP(+)-dependent dehydrogenase also called the 11 beta HSD1-like dehydrogenase (11 beta HSD1L), as well as evidence for yet identified 11 beta HSDs. Attention is devoted to more recently described aspects of this multi-functional family. The importance of 11 beta HSD substrates other than glucocorticoids including bile acids, 7-keto sterols, neurosteroids, and xenobiotics is discussed, along with examples of pathology when functions of these multi-tasking enzymes are disrupted. 11 beta HSDs modulate the intracellular concentration of glucocorticoids, thereby regulating the activation of the glucocorticoid and mineralocorticoid receptors, and 7 beta-27-hydroxycholesterol, an agonist of the retinoid-related orphan receptor gamma (ROR gamma). Key functions of this nuclear transcription factor include regulation of immune cell differentiation, cytokine production and inflammation at the cell level. 11 beta HSD1 expression and/or glucocorticoid reductase activity are inappropriately increased with age and in obesity and metabolic syndrome (MetS). Potential causes for disappointing results of the clinical trials of selective inhibitors of 11 beta HSD1 in the treatment of these disorders are discussed, as well as the potential for more targeted use of inhibitors of 11 beta HSD1 and 11 beta HSD2.